Metabolic Rewiring by alpha-Synuclein Enables Mitohormetic Protection

-Synuclein (Syn) is widely associated with Parkinsons disease pathology, yet its physiological impact on cellular metabolism remains unclear. Here we show that stable Syn expression in HEK293 cells induces coordinated metabolic remodeling that enhances mitochondrial resilience. Syn interacts with lactate dehydrogenase A (LDHA) and Syn-expressing clones exhibit elevated LDHA activity. Moreover, these clones exhibit increased lactate secretion, enhanced glycolysis, and reduced mitochondrial-reactive oxygen species, coupling metabolic rewiring to improved mitochondrial adaptation. Strikingly, following chronic low-dose rotenone preconditioning, Syn- expressing clones acquire robust resistance to subsequent respiratory complex I inhibition, revealing a potent Syn-dependent mitohormetic response. These findings identify Syn as a conditional metabolic modulator that supports mitochondrial adaptation under sustained stress.